HIF-1α in CD4+ T cells drives gout pathogenesis via metabolic reprogramming and Th17 differentiation.

Hypoxia-inducible factor 1-alpha (HIF-1α), a central regulator of immunometabolic reprogramming, has been associated with multiple inflammatory conditions. However, its function in CD4+ T cell-mediated glycolytic dysregulation during gout pathogenesis remains unclear. Herein, we demonstrated that HIF-1α expression was elevated in CD4+ T cells derived from patients with gout and urate oxidase (Uox)-knockout (KO) mice. Both pharmacological inhibition (PX-478) and CD4+ T cell-specific genetic ablation of HIF-1α alleviated gout symptoms, including reduced serum uric acid levels, diminished T helper 17 (Th17) cell polarization, and mitigated renal injury. RNA sequencing (RNA-seq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that HIF-1α disruption impaired Th17 differentiation, which was further validated using flow cytometry. Seahorse metabolic profiling and 2-deoxy-D-glucose (2-DG) treatment confirmed that HIF-1α promotes gout pathogenesis by driving glycolysis-dependent Th17 expansion and interleukin-17 (IL-17) production. Importantly, the natural compound dioscin was found to directly bind HIF-1α, suppress its expression, and reverse the disease phenotypes in vitro and in vivo. Conversely, HIF-1α activation using 1,1-dimethylethyl ester 6-[2,5-dihydro-5-oxo-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl]-3-pyridinecarboxylic acid (IOX4) exacerbated gout features, which were effectively counteracted by dioscin. Collectively, these findings identify CD4+ T cell-derived HIF-1α as a key glycolytic regulator in gout and highlight dioscin as a promising candidate for HIF-1α-targeted therapeutic intervention.